Ethanol craving in patients is a significant clinical problems with a poorly understood underlying neurobiology. This application represents the resubmission of the competitive renewal of a research program illum inating the clinical neurobiology of this important problem. We outline a new study, building on the initial year of progress, that will further evaluate the contributions of noradrenergic systems to ethanol craving. This is part of a ling- term attempt to elucidate a model describing the unique and interactive contributions of noradrenergic and serotonergic systems to the neurobiology of ethanol craving in alcoholics. Noradrenergic systems appear to modulate arousal-related reactivity, while serotonergic system a modulate the processing of ethanol-related cues and impulse control regarding ethanol self-administration. Background: The investigative team collaborating in this application has validated a laboratory-based paradigm designed to stimulate ethanol craving in alcoholic patients. During the initial year of the two-year previous R01, data were collected implicating noradrenergic systems in ethanol cue reactivity and suggesting that craving may be modulated by tryptophan depletion. Objectives: To determine whether transient inhibition of noradrenergic function, produced by the 2-adrenergic agonist, clonidine, reduces the magnitude of alcohol cue-induced craving in sober alcohol dependent patients. Methods: In an ongoing study, individuals meeting DSM-IV criteria for alcohol will be recruited, 1-3 moths post-detoxification. Patients will complete an initial alcohol cue exposure session. Patients exhibiting al least a 20% increase in craving in the initial cue exposure session will complete two additional cue-exposure tests. Cue exposure sessions will be preceded by placebo or clonidine. Each test day will be scheduled one week apart, and the sequence will be randomized. Preliminary Results: Preliminary results indicate that clonidine appeared to reduce cue-induced craving for alcohol. Implications: These data are part of a larger body of work that attempts to evaluate an heuristic model, described in this application, in which noradrenergic and serotonergic systems differentially contribute to the modulation of cue-induced craving.